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AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.
Terhal, Paulien; Venhuizen, Anton J; Lessel, Davor; Tan, Wen-Hann; Alswaid, Abdulrahman; Grün, Regina; Alzaidan, Hamad I; von Kroge, Simon; Ragab, Nada; Hempel, Maja; Kubisch, Christian; Novais, Eduardo; Cristobal, Alba; Tripolszki, Kornelia; Bauer, Peter; Fischer-Zirnsak, Björn; Nievelstein, Rutger A J; van Dijk, Atty; Nikkels, Peter; Oheim, Ralf; Hahn, Heidi; Bertoli-Avella, Aida; Maurice, Madelon M; Kornak, Uwe.
Afiliación
  • Terhal P; Division of Laboratories, Pharmacy and Biomedical Genetics, University Medical Centre Utrecht, 3584EA Utrecht, the Netherlands. Electronic address: p.a.terhal@umcutrecht.nl.
  • Venhuizen AJ; Center for Molecular Medicine and Oncode Institute, University Medical Centre Utrecht, 3584CG Utrecht, the Netherlands.
  • Lessel D; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; Institute of Human Genetics, University Hospital Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria.
  • Tan WH; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
  • Alswaid A; Department of Pediatrics, King Abdullah Specialized Children's Hospital, Riyadh 14611, Saudi Arabia; King Saud Bin Abdulaziz University For Health Sciences, Riyadh 22490, Saudi Arabia.
  • Grün R; Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
  • Alzaidan HI; Medical Genetics Department, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh 11211, Saudi Arabia.
  • von Kroge S; Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany.
  • Ragab N; Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
  • Hempel M; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; Institute of Human Genetics, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • Kubisch C; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
  • Novais E; Department of Orthopedic Surgery, Boston Children's Hospital, Boston, MA 02115, USA.
  • Cristobal A; Center for Molecular Medicine and Oncode Institute, University Medical Centre Utrecht, 3584CG Utrecht, the Netherlands.
  • Tripolszki K; Centogene GmbH, 18055 Rostock, Germany.
  • Bauer P; Centogene GmbH, 18055 Rostock, Germany; University Hospital Rostock, Internal Medicine, Hemato-oncology, 18057 Rostock, Germany.
  • Fischer-Zirnsak B; Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
  • Nievelstein RAJ; Department of Radiology & Nuclear Medicine, University Medical Centre Utrecht, 3584CX Utrecht, the Netherlands.
  • van Dijk A; Expert Center for Skeletal Dysplasia, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584EA Utrecht, the Netherlands.
  • Nikkels P; Department of Pathology, University Medical Centre Utrecht, 3584CX Utrecht, the Netherlands.
  • Oheim R; Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany.
  • Hahn H; Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
  • Bertoli-Avella A; Centogene GmbH, 18055 Rostock, Germany.
  • Maurice MM; Center for Molecular Medicine and Oncode Institute, University Medical Centre Utrecht, 3584CG Utrecht, the Netherlands.
  • Kornak U; Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany; Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany. Electronic address: uwe.kornak@med.uni-goettingen.de.
Am J Hum Genet ; 110(9): 1470-1481, 2023 09 07.
Article en En | MEDLINE | ID: mdl-37582359
Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the ß-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteosclerosis / Tanquirasas / Luxación de la Cadera Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteosclerosis / Tanquirasas / Luxación de la Cadera Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos